SEIZURES IN HIPPOCAMPI OF EPILEPTIC CHILDREN

癫痫儿童海马体癫痫发作

基本信息

批准号：
2609520
负责人：
GARY W. MATHERN
金额：
$ 9.3万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-12-01 至 1998-11-30
项目状态：
已结题

项目摘要

Human hippocampal epilepsy is one of the most difficult epileptic syndromes to control. These intractable and often severe seizures are associated with electrophysiologic hyperexcitability, severe Ammon's horn neuron loss, and evidence of aberrant axonal plasticity, termed hippocampal sclerosis (HS). The etiology of HS is unknown, and it is likewise unclear if HS is the pathophysiologic substrate of chronic epilepsy or the pathologic consequence of multiple seizures. A unique developmental feature of the hippocampus is the postnatal neurogenesis, migration and axon formation of granule cells (GC). The GCs are the parent neurons for mossy fibers (MF), one of the principal aberrantly sprouted axon systems in HS. We recently have had the unique opportunity to study surgically resected hippocampi from epileptic children to discern the evolution of pathologic changes as they relate to seizures and postnatal GC maturation. Preliminary results show evidence of aberrant MF sprouting at the time of postnatal GC development. The size of the MF fibers and boutons increased in older seizure patients, suggesting maturation of these axons. Seizure associated regio inferior neuron loss was found in all epileptic children, but greater neuron loss was found after age 2 years, when the GCs had nearly completed neurogenesis. This proposal is designed to further study hippocampi from epileptic children and will determine the following specific aims. l) Determine the progressive pathologic changes in the hippocampus that might suggest an etiology of adult HS. Our two hypotheses are that adult HS is either the consequence of progressive seizure related pathologic changes or it is a result of some severe perinatal insult that is associated with structural damage. 2) Determine the time course of postnatal hippocampal development. We will look for the in vivo expression of proteins associated with neurogenesis, migration, and axon growth cone formation. Our hypothesis is that postnatal hilar cells and GCs will differentially express these proteins compared with the remaining hippocampus which forms prenatally. 3) Determine the postnatal differential expression of neurotrophic factors (NTF) in the developing hippocampus. Our hypothesis is that mRNA NTF expression is altered in epileptic hippocampi in a manner that promotes and maintains aberrant sprouting during postnatal axon development. Age- matched autopsy hippocampi without evidence of brain pathology will serve as controls. Parallel developmental studies will be performed in rat pups to determine if postnatal hippocampal maturation is different in another mammalian species. These studies on epileptic children form a data base that will be expanded upon in future human and animal experiments to study the cellular mechanisms and pathophysiology of HS. A CIDA is also a training grant. The most significant component of the training will be in acquiring research skills that will complement my existing clinical knowledge and training in Neurosurgery. The research program contains a didactic exposure to basic Neuroscience graduate courses, hands on technical and theoretical exposure to molecular neurobiology, teaching, and close supervision by senior neuroscientists. The goal is sufficient research training and exposure to become an independent clinical investigator familiar with basic research applied to clinical epilepsy related problems.

人海马癫痫是最困难的癫痫病之一控制综合征。这些棘手且经常严重的癫痫发作是与电生理过度兴奋性，严重的Ammon的角有关神经元丧失和异常轴突可塑性的证据称为海马硬化症（HS）。 HS的病因是未知的，这是同样不清楚HS是否是慢性的病理生理底物癫痫病或多种癫痫发作的病理后果。一个独特的海马的发育特征是产后神经发生，颗粒细胞（GC）的迁移和轴突形成。 GC是父母苔藓纤维的神经元（MF），这是主要发芽的主要纤维之一 HS中的轴突系统。我们最近有独特的学习机会手术切除的海马从癫痫儿童辨别与癫痫发作相关的病理变化的演变 GC成熟。初步结果显示了异常MF发芽的证据在产后GC开发时。 MF纤维的大小和年龄较大的癫痫病患者增加了胸子，表明这些轴突。在所有癫痫儿童，但在2岁之后发现了更大的神经元丧失几年，GC几乎完成了神经发生。该提议是旨在进一步研究癫痫儿童的海马，并将确定以下特定目标。 l）确定渐进式海马的病理变化可能表明成人HS。我们的两个假设是成年HS是结果进行性癫痫发作相关的病理变化，或者是一些与结构性损害有关的严重围产期侮辱。 2）确定产后海马发育的时间过程。我们将寻找与神经发生相关的蛋白质的体内表达迁移和轴突生长锥形成。我们的假设是产后荷尔细胞和GC将差异表达这些蛋白质与剩余的海马相比，在产前形成。 3）确定神经营养因子的产后差异表达（NTF）在发展中的海马。我们的假设是mRNA NTF 表达在癫痫海马中以促进的方式改变并在产后轴突发育过程中保持异常发芽。年龄- 没有脑病理学证据的尸检海马匹配将服务作为控件。平行发育研究将在大鼠幼崽中进行确定产后海马成熟在另一个中是否有所不同哺乳动物。这些关于癫痫儿童的研究形成了数据库这将在未来的人类和动物实验中扩展到研究 HS的细胞机制和病理生理学。 CIDA也是培训补助金。最重要的组成部分培训将是获得研究技能，这将补充我的神经外科的现有临床知识和培训。研究程序包含与基本神经科学毕业生的教学效果课程，技术和理论上的分子暴露高级神经科学家的神经生物学，教学和密切监督。目标是足够的研究培训和接触才能成为独立临床研究者熟悉基础研究适用于临床癫痫相关问题。